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Gut 56:1171-1173 doi:10.1136/gut.2007.122747
  • Letter

Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn’s disease

  1. Robert N Baldassano1,
  2. Jonathan P Bradfield2,
  3. Dimitri S Monos3,
  4. Cecilia E Kim4,
  5. Joseph T Glessner4,
  6. Tracy Casalunovo4,
  7. Edward C Frackelton4,
  8. F George Otieno4,
  9. Stathis Kanterakis5,
  10. Julie L Shaner6,
  11. Ryan M Smith6,
  12. Andrew W Eckert6,
  13. Luke J Robinson6,
  14. Chioma C Onyiah6,
  15. Debra J Abrams7,
  16. Rosetta M Chiavacci8,
  17. Robert Skraban8,
  18. Marcella Devoto9,
  19. Struan F A Grant10,
  20. Hakon Hakonarson10
  1. 1Division of Gastroenterology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  2. 2Center for Applied Genomics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  3. 3Department of Pediatrics, University of Pennsylvania, School of Medicine and Department of Pathology and Laboratory Medicine, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  4. 4Center for Applied Genomics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  5. 5Department of Pediatrics University of Pennsylvania, School of Medicine and Department of Pathology and Laboratory Medicine, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  6. 6Center for Applied Genomics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  7. 7Division of Gastroenterology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  8. 8Center for Applied Genomics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  9. 9Division of Human Genetics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, and CCEB, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  10. 10Center for Applied Genomics, and Division of Human Genetics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  1. Correspondence to:
    Dr Hakon Hakonarson and Dr Struan Grant
    Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia 19104, Pennsylvania, USA; hakonarson{at}chop.edu or grants{at}chop.edu

    The hunt for genetic variants conferring risk to inflammatory bowel disease (IBD) has been ongoing for more than 10 years, with a number of susceptibility genes implicated through various approaches. Earlier this year, through the genotyping of 16 360 non-synonymous single nucleotide polymorphisms (SNPs), Hampe et al1 made an important addition to this repertoire by reporting a highly significant association between Crohn’s disease and the autophagy-related 16-like 1 (ATG16L1) gene. Specifically, a common coding variant, rs2241880 (T300A), was shown to confer a strong risk for the disease, and this association was replicated in the same study in separate cohorts of patients with Crohn’s disease but not with ulcerative colitis. Although these findings are compelling, there are continuing concerns regarding the performance of association studies in complex traits.2 Many errors and biases can blight any individual study, whereas independent replication ensures that the original findings are indeed robust and provide a more accurate estimate of the likely effect size.3,4. Such independent replication efforts are now considered mandatory in the study of complex traits.2

    We have an ongoing genome-wide association study of children with Crohn’s disease using the Illumina Infinium II HumanHap500 BeadChip.5,6 The probe for rs2241880 is present on this platform, so we were able to query our current dataset for its association with Crohn’s disease as a single test. All analyses were carried out using the software package “plink” (http://pngu.mgh.harvard.edu/~purcell/plink/index.shtml). In order to avoid potential bias deriving from population stratification, controls were genetically matched to Caucasian patients with Crohn’s disease by clustering of the pairwise identity-by-state distances. Complete linkage agglomerative clustering was …